Abstract
Neutrophil elastase (NE) is a major inflammatory protease released by neutrophils and is present in the airways of patients with cystic fibrosis (CF), chronic obstructive pulmonary disease, non-CF bronchiectasis, and bronchopulmonary dysplasia. Although NE facilitates leukocyte transmigration to the site of infection and is required for clearance of Gram-negative bacteria, it also activates inflammation when released into the airway milieu in chronic inflammatory airway diseases. NE exposure induces airway remodeling with increased mucin expression and secretion and impaired ciliary motility. NE interrupts epithelial repair by promoting cellular apoptosis and senescence and it activates inflammation directly by increasing cytokine expression and release, and indirectly by triggering extracellular trap release and exosome release, which magnify protease activity and inflammation in the airway. NE inhibits innate immune function by digesting opsonins and opsonin receptors, degrading innate immune proteins such as lactoferrin, and inhibiting macrophage phagocytosis. Importantly, NE-directed therapies have not yet been effective in preventing the pathologic sequelae of NE exposure, but new therapies are being developed that offer both direct antiprotease activity and multifunctional anti-inflammatory properties.
Highlights
Neutrophil elastase (NE) proteinase activity is critical for normal innate immune function, release of NE into the airway milieu contributes to lung
We have demonstrated by in silico modeling and Michealis–Menten kinetics that O desulfated heparin (ODSH)
NE is critical for the host immune response to infection, but NE is a major instigating factor for inflammation and airway injury in chronic inflammatory lung diseases
Summary
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. NE is localized to the cell surface after neutrophil activation by binding to highly abundant but low-affinity chondroitin sulfate and heparan sulfate proteoglycans [7]. Several factors modulate NE airway protease activity, including the abundance and localization of NE, the concentrations of lung antiproteases, α1 -antitrypsin, α2 -macroglobulin, or secretory leukocyte proteinase inhibitor (SLPI), at the site of enzyme activity [8], and even the target protein O-linked glycosylation [11]. NE proteinase activity is critical for normal innate immune function, release of NE into the airway milieu contributes to lung. We will discuss the pathogenesis of dysregulated NE release into the airways in chronic lung diseases, and the mechanisms by which NE alters airway and lung parenchymal structures, and modulates innate immune processes and inflammation, leading to worsening disease. We will review the status of clinical trials to target NE in chronic lung diseases, and alternative strategies to control NE-mediated lung injury
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